Phase 2a Feasibility Study of T3D-959 in Subjects With Mild to Moderate Alzheimer's Disease
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 36
- 试验地点
- 3
- 主要终点
- Change From Baseline (End of Treatment - Baseline) for FDG-PET Imaging With Whole Brain and White Matter as Reference Region
研究概览
简要总结
The study is a randomized, parallel, 4-dose design in subjects with mild-to-moderate Alzheimer's Disease. Subjects will be randomized to one of 4 doses of T3D-959. Subjects will be evaluated for changes from baseline in cerebral metabolic rate of glucose (FDG-PET imaging), functional connectivity of the hippocampus (BOLD-fMRI), and cognitive function (ADAS-Cog11 and DSST) as well as assessed for safety and tolerability to T3D-959.
An expanded access extension is planed to provide access to study medication to subjects who have completed the main study and requested continued use.
详细描述
T3D-959 is an orally-delivered, once-a-day administered, small molecule dual nuclear receptor agonist that has been shown in animal and Phase 1 studies in normal human subjects to be safe and well tolerated. The purpose of this clinical study in AD patients is to demonstrate mechanistic proof of concept that T3D-959, can produce desired changes in cerebral glucose metabolism and functional connectivity that may indicate potential for cognitive improvement. The therapeutic approach to be tested is based on two suppositions; (A) ameliorating multiple pathologies in the disease with a single therapy may provide a superior clinical benefit than therapeutic approaches which target a single pathology and (B) correcting insulin resistance in the brain, (highly correlated with AD and potential key driver of AD pathophysiology) and peripherally may be disease remedial.
The brain requires integral insulin signaling for metabolic homeostasis and neuronal plasticity. Insulin resistance disrupts energy balance and signaling networks needed for a broad range of functions. Impaired insulin signaling in neurons enhances apoptosis, promotes oxidative cell death induced by Abeta1-42, increases secretion of Abeta1-42, blocks removal of extracellular Abeta oligomers and increases plaque loads. A growing body of evidence suggests that brain insulin resistance promotes or possibly is the trigger of key pathologies in AD and is supported by observed changes in levels of insulin signaling molecules in AD forebrains and associated changes in memory. Pre-clinical studies in animals have demonstrated the insulin sensitizing activity of T3D-959 and ability to improve multiple pathologies of AD in a rat model of disease.
This non-placebo controlled trial will be conducted in one to three clinical centers. Thirty six (36) patients with mild-to-moderate Alzheimer's disease will be randomly assigned to once daily, orally administered treatment with 3mg, 10mg, 30mg or 90mg doses of T3D-959. Participants will be treated for two weeks and will undergo at baseline and at two weeks; FDG-PET scans to measure brain glucose metabolism, BOLD fMRI scans to measure functional connectivity of the hippocampus, venous blood draws for biomarker analysis and ApoE genotyping, and ADAS-Cog11 and DSST cognitive testing. For monitoring potential toxicities of the drug subjects will undergo physical examination, neurological examination, adverse event review, blood chemistries, and pharmacokinetic (PK) analyses for T3D-959 plasma levels.
BOLD fMRI definition of terms:
GoF (Goodness of Fit): The degree to which the spatial extent and magnitude of one subject's default mode network (DMN) regions matches the one of an elderly control group.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 50 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Meets criteria for mild-to-moderate AD with Mini-Mental State Examination (MMSE) score of 14 through 26
- •Clinical Dementia Rating = 0.5 to 2.0
- •Modified Hachinski less than or equal to 4
- •A clinical diagnosis of AD per NINCDS-ADRDA criteria
- •Washout of psychoactive medication (other than anti-depressants): at least 4 weeks prior to baseline
- •Stability of all permitted medications for 4-12 weeks prior to baseline
- •Visual and auditory acuity adequate for neuropsychological testing
- •Home monitoring available for supervision of medications
排除标准
- •Unstable diabetes or insulin use
- •Unable to participate in FDG-PET scanning
- •Inability to undergo a clinical MRI of the brain
- •Diagnosis of significant neurological/psychiatric disease other than AD
- •History of moderate or severe congestive heart failure, NYHA class III or IV, within 12 months prior to baseline.
- •Previous cardiovascular event within the past 6 months prior to baseline
- •Subject is pregnant, or lactating.
- •ALT and/or AST levels that are twice the upper limit of normal; bilirubin levels that exceed 2 mg/dL; serum creatinine >1.5 mg/dL in men or > 1.4 mg/dL in women.
- •Current or history of severe or unstable disorder (medical or psychiatric) requiring treatment that may make the subject unlikely to complete the study.
- •Current use of fluvoxamine.
- •Current unstable use of warfarin.
- •Current use (within 30 days of baseline, visit 2) of certain highly protein-bound medications
- •Malignancy within the last 5 years (other than non-melanoma skin cancer, stable, non-progressive prostate cancer not requiring treatment or in situ cervical cancer).
- •Known history of HIV, hepatitis B, or hepatitis C.
- •Blood pressure greater than 160/100 mmHg.
- •Known or suspected intolerance or hypersensitivity to the study drugs, closely related compounds, or any of their stated ingredients.
- •History of alcohol, drug abuse or dependence (except nicotine dependence) within 2 years.
- •Investigational amyloid lowering therapies use within two months prior to baseline
- •Have participated in any other investigational study or received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to baseline
- •Any surgical or medical condition which may significantly alter the absorption of any drug substance
- •Resides in hospital or moderate to high dependency continuous care facility.
- •Non ambulatory, or wheelchair-bound
- •History of swallowing difficulties.
- •Evidence of clinically relevant pathology that in the investigator's opinion could interfere with the study results or put the subject's safety at risk.
- •Expanded Access Extension :
- •Subjects must continue to meet the main study inclusion/exclusion criteria to insure continued safety to continue on a 6 months study extension
研究组 & 干预措施
T3D-959 3mg
Nine subjects will take 3mg by mouth once daily for two weeks, with or without food.
干预措施: T3D-959 (Drug)
T3D-959 10mg
Nine subjects will take 10mg by mouth once daily for two weeks, with or without food.
干预措施: T3D-959 (Drug)
T3D-959 30mg
Nine subjects will take 30mg by mouth once daily for two weeks, with or without food.
干预措施: T3D-959 (Drug)
T3D-959 90mg
Nine subjects will take 90mg by mouth once daily for two weeks, with or without food.
干预措施: T3D-959 (Drug)
结局指标
主要结局
Change From Baseline (End of Treatment - Baseline) for FDG-PET Imaging With Whole Brain and White Matter as Reference Region
时间窗: after 14 days of treatment
Changes in relative brain glucose metabolism (delta R CMRgl) were measured by FDG-PET. At each time point, a ratio of the PET reading in a pre-defined region of interest (sROI), known to be affected by AD, and in a reference region (RR) that is spared in AD, is determined. This ratio is defined as "sROI index" (spared region). A second RR, brain white matter (WM), was also used in this calculation: sROI index" (WM) value. delta sROI is defined as change in the sROI index values, over the treatment period. In this study we are looking for changes in delta sROI with increasing doses of T3D-959. Dose dependent changes in delta sROI (AD spared) are compared to those observed with the WM as the RR: delta sROI (WM). Dose related changes in delta sROI suggests T3D-959 is entering the brain and effecting glucose metabolism in a dose dependent fashion.
The Effect of Treatment With T3D-959 on Changes in Resting State Blood Oxygen Level Dependent (BOLD) Signal in Functional Magnetic Resonance Imaging (fMRI) of the Brain Areas Associated With Cognitive Tasks.
时间窗: after 14 days of treatment
Changes in BOLD fMRI parameters such as GoF (see Study Description) over the course of two weeks of treatment, were obtained in this study. BOLD fMRI has been used in cross sectional and longitudinal studies of Alzheimer's subjects, for instance in the Alzheimer's Disease Neuroimaging Initiative studies. However, no studies monitoring Default Mode Networks measured parameters such as GoF, in the context of an effective AD therapeutic, as a result it is difficult to interpret the observed small changes listed in BOLD fMRI parameters obtained in this trial. Instead the changes in the listed BOLD fMRI parameters (EOT - BL) are reported without interpretation. These values represent changes in fMRI connectivity patterns over time and are unitless.
次要结局
- Change From Baseline in the Score of the Digit Symbol Substitution Test(after 14 days of treatment)
- Change From Baseline in the Total Score of the 11-item Alzheimer's Disease Assessment Scale - Cognitive Subscale(after 14 days of treatment)